Recognition of thalidomide defects.
(1992)

Thalidomide: a brief history Thalidomide (alpha-phthalimido-glutarimide) was developed by the German firm Chemie Grunenthal as an anticonvulsant drug. Early trials showed it to be unsuitable for this purpose but indicated that it had sedative properties. Furthermore, it had one remarkable property: overdoses simply caused prolonged sleep, not death. The drug was first marketed in Germany in 1957 under the name Contergan, and in the UK in April 1958 as Distaval. Later, compound preparations which combined thalidomide with other drugs were marketed for a wide variety of indications: Asmaval for asthma, Tensival for hypertension, Valgraine for migraine, and so forth. The promotion of these products laid great stress on the safety of thalidomide, based on the remarkable property described above. German paediatricians and geneticists began to see children with gross limb malformations of a most unusual pattern. When two cases were shown at a paediatric meeting in Kassel by Kosenow and Pfeiffer in October 1960, few people present had ever seen similar limb defects. Wiedemann in 1961 described 13 affected infants who had been referred to him over a period of 10 months, and noted that this amounted to an epidemic. He drew attention to a number of associated malformations in these children, including congenital heart disease, microphthalmos and coloboma, intestinal atresia, renal malformations, abnormal pinnae, and facial naevus. In November 1961, Lenz suggested that these deformities resulted from the mothers having taken thalidomide. By a remarkable coincidence, the same suggestion was made at much the same time by McBride in Australia. Confirmation of this suggestion came rapidly from all parts of the British Isles, Kenya, Japan, Sweden, Belgium, Switzerland, Lebanon, Israel, Peru, Canada, Brazil, the Netherlands, and the USA. The drug had been released only for clinical trials in the USA because of concerns following reports from Europe of irreversible peripheral neuritis as a side effect of thalidomide. Consequently there were very few cases. By contrast, it had been on sale over the counter in Germany, and there were consequently more affected children there than anywhere else. In the UK the drug was available on prescription only, but it was used very widely for, among other problems, common symptoms of early pregnancy. Thirty years later, subjects are still coming forward (albeit, in small numbers) with claims that they have birth defects which have (or may have) been caused by thalidomide taken by their mothers during early pregnancy, and that they should therefore be accepted as beneficiaries of whatever forms of financial assistance may be available. In the UK, this is the Thalidomide Trust. Thalidomide caused a wide variety of birth defects, not one of which was unique to that drug. Nevertheless, the nature and pattern of the defects are, in most cases, characteristic enough to be recognisable to an experienced eye. Indeed, many of the present beneficiaries of the Trust have been accepted on the basis of clinical judgements, without direct evidence of thalidomide exposure. As the number of doctors with wide experience of this problem is small (possibly only three in the UK) and will become smaller with the passage of time, and as new claims continue to arise, it seems timely to record, in as much detail as possible, the observations which underlie these clinical judgements. As well as describing the defects and patterns associated with thalidomide, it will be appropriate to discuss 'differential diagnosis', that is, recognisable defects and syndromes which, to a greater or lesser degree, resemble thalidomide defects. Some of these are unlikely to confuse an experienced eye: others can present considerable difficulty. In considering a new claim, attention will obviously be paid to the claimant's date of birth. In the UK, thalidomide was first marketed in April 1958, initially in very small quantities, so it is not to be expected that it would damage anybody born before January 1959 (unless supplies had been obtained from West Germany). Sales in the UK stopped in November 1961. Had consumption stopped at the same time, no 'thalidomide babies' should have been born after August 1962. However, many people still had tablets containing thalidomide in their homes, and either did not hear promptly of its dangers, or did not realise that their tablets contained thalidomide. In fact, children with defects accepted as attributable to thalidomide (though not necessarily with documentary evidence of prescription) continued to be born up to about May 1963, and, very exceptionally, beyond this date. In trying to establish a yardstick or benchmark for bona fide thalidomide defects, it is necessary to start with cases in which there is 5 North Grange Mews, North Grange Road, Leeds LS6 2EW. R W Smithells